This invention relates to certain fungicidal amides, their compositions, and methods of their use as fungicides.
The control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action.
Japanese Patent Application JP 2,233,654 and International Publication WO 97/35838 disclose certain amides and their use as fungicides. V. Prelog and J. Thix in Helv. Chim. Acta (1982), 65(8), 2622-44 disclose certain cyclobutane carboxamides.
The fungicidal amides of the present invention are not disclosed in these publications.
This invention is directed to compounds of Formula I including all geometric and stereoisomers, agricultural compositions containing them and their use as fungicides: 
wherein
R1 is hydrogen; halogen; C1-C2 alkoxy; C1-C2 haloalkoxy; cyano; or C1-C2 alkyl optionally substituted with halogen, C1-C2 alkoxy or cyano;
R2 is hydrogen; halogen; or C1-C4 alkyl optionally substituted with halogen, C1-C2 alkoxy or cyano;
R3 is hydrogen; halogen; C1-C4 alkoxy; C1-C4 haloalkoxy; or C1-C4 alkyl optionally substituted with halogen, C1-C2 alkoxy or cyano; or
R2 and R3 can be taken together as xe2x80x94CH1CH2xe2x80x94;
R4 is C1-C2 alkyl;
R5 is R6, CH(R8)OR6, CH(R8)CH(R7)R6 or C(R8)xe2x95x90C(R7)R6;
R6 is phenyl; naphthalenyl; a 5- to 6-membered aromatic heterocyclic ring containing 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur; or a 9- to 10-membered fused aromatic bicyclic ring containing 1 to 2 heteroatoms each R6 optionally substituted with one to three substituents selected from the group halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Si(CH3)3, cyano, NHC(xe2x95x90O)R9 and NHC(xe2x95x90S)R9;
R7 is halogen, C1-C4 alkyl or C1-C4 haloalkyl;
R8 is hydrogen; C1-C6 alkyl; phenyl optionally substituted with halogen, cyano, C1-C3 alkyl or C1-C3 alkoxy; or pyridinyl optionally substituted with halogen, cyano, C1-C3 alkyl or C1-C3 alkoxy; and
each R9 is hydrogen or C1-C4 alkyl;
provided that
i) at least one of R1, R2 and R3 is other than hydrogen; and
ii) when R2 and R3 are taken together as xe2x80x94CH2CH2xe2x80x94, then R5 is other than R6.
In the above recitations, the term xe2x80x9calkylxe2x80x9d, used alone or in the compound words such as xe2x80x9chaloalkylxe2x80x9d includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers. xe2x80x9cAlkoxyxe2x80x9d includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy isomers.
The term xe2x80x9chalogenxe2x80x9d, either alone or in compound words such as xe2x80x9chaloalkylxe2x80x9d, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as xe2x80x9chaloalkylxe2x80x9d, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of xe2x80x9chaloalkylxe2x80x9d include F3C, ClCH2, CF3CH2 and CF3CCl2. The term xe2x80x9chaloalkoxyxe2x80x9d is defined analogously to the term xe2x80x9chaloalkyl. Examples of xe2x80x9chaloalkoxyxe2x80x9d include CF3O, CCl3CH2O, HCF2CH2CH2O and CF3CH2O.
The terms xe2x80x9caromaticxe2x80x9d is defined as those rings or rings which satisfy the Hxc3xcickel rule. The term xe2x80x9caromatic heterocyclic ringxe2x80x9d includes aromatic heterocycles (where aromatic indicates that the Hxc3xcckel rule is satisfied). The heterocyclic rings can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen. Examples of 5- to 6-membered aromatic heterocyclic rings include thienyl, isothiazolyl, thiazolyl, pyrrolyl and pyridinyl. The term xe2x80x9cfused aromatic bicyclic ringxe2x80x9d includes fused aromatic heterocycles (where aromatic indicates that the Hxc3xcckel rule is satisfied). Examples of fused aromatic bicyclic rings containing 1 to 2 heteroatoms include benzofuranyl, benzo[b]thiophenyl and benzothiazolyl.
The total number of carbon atoms in a substituent group is indicated by the xe2x80x9cCi-Cjxe2x80x9d prefix where i and j are numbers from 1 to 4. For example, C1-C2 alkyl designates methyl and ethyl.
When a group contains a substituent which can be hydrogen, for example R1 or R2, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted. When a group is optionally substituted with a substituent, (e.g., C1-C2 alkyl optionally substituted with halogen), then, when the group is not substituted with that substituent, it is recognized that this is equivalent to said group having a hydrogen substituent.
Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Compounds of Formula I can exist as cis and trans cyclobutane isomers. This invention comprises cis/trans mixtures as well as the pure isomers. The compounds of this invention can exist as R and S enantiomers at the carbon to which R4 and R5 are attached. Of particular note are the compounds of Formula I having the R configuration. The R configuration is as defined by the Cahn-Ingold-Prelog system. (See March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985).) This invention comprises racemic mixtures as well as pure enantiomers. Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the present invention comprises all compounds selected from Formula I. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
Preferred compounds for reasons of better activity and/or ease of synthesis are:
Preferred 1. Compounds of Formula I above wherein
R1 is halogen or C1-C2 alkyl optionally substituted with halogen;
R2 is halogen or C1-C2 alkyl optionally substituted with halogen;
R3 is halogen or C1-C2 alkyl optionally substituted with halogen;
R4 is CH3;
R5 is R6; and
R6 is phenyl optionally substituted with one to two substituents selected from the group halogen, C1-C4 alkyl, CF3, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano.
Preferred 2. Most preferred compounds include compounds of Preferred 1 selected from the group
[1(R)-cis]-N-[1-(4-bromophenyl)ethyl]-3-chloro-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide;
[1(R)-trans]-N-[1-(4-bromophenyl)ethyl]-3-chloro-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide;
[1(R)-trans]-N-[1-(4-bromophenyl)ethyl]-3-chloro-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide;
[1(R)-trans]-3-chloro-N-[1-(4chlorophenyl)ethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide;
[1(R)trans]-3-chloro-N-[1-(2,4-dichlorophenyl)ethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide;
(1R)-N-[1-(4-bromophenyl)ethyl]-1,3,3-trichlorocyclobutanecarboxamide;
[1(R)-trans]-N-[1-(4-bromophenyl)ethyl]-3-chloro-1,3-dimethylcyclobutanecarboxamide;
[1(R)cis]-N-[1-(4-bromophenyl)ethyl]-3-chloro-1,3-dimethylcyclobutanecarboxamide;
[1(R)-trans]-3-bromo-N-[1-(4-bromophenyl)ethyl]-1,3-dimethylcyclobutanecarboxamide;
[1(R)-cis]-3-bromo-N-[1-(4-bromophenyl)ethyl]-1,3-dimethylcyclobutanecarboxamide;
[1(R)-trans]-3-chloro-N-[1-(2,4-dichlorophenyl)ethyl]-1,3-dimethylcyclobutanecarboxamide;
[1(R)-cis]-3-chloro-N-[1-(2,4-dichlorophenyl)ethyl]-1,3-dimethylcyclobutanecarboxamide;
[1(R)-cis]-N-[1-(4-bromo-2-methoxyphenyl)ethyl]-3-chloro-1,3-dimethylcyclobutanecarboxamide; and
[1(R)-cis]-N-[1-(4-bromophenyl)ethyl]-3-chloro-3-(chloromethyl)-1-methylcyclobutanecarboxamide.
Preferred 3. Compounds of Formula I above wherein
R1 is halogen or C1-C2 alkyl;
R2 is halogen or C1-C2 alkyl;
R3 is hydrogen or C1-C2 alkyl optionally substituted with halogen;
R4 is CH3;
R5 is CH2OR6; and
R6 is phenyl optionally substituted with one to two substituents selected from the group halogen, C1-C4 alkyl, C1-C4 haloalkoxy and cyano.
Preferred 4. Most preferred compounds include compounds of Preferred 3 selected from the group
[1(R)cis]-3-chloro-N-[2-(2-fluorophenoxy)-1-methylethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide;
[1(R)-trans]-3-chloro-N-[2-(2-fluorophenoxy)-1-methylethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide;
[1(R)-trans]-3-chloro-N-[2-(2-fluorophenoxy)-1-methylethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide;
[1(R)-trans]-3-chloro-N-[2-(2,5-difluorophenoxy)-1-methylethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide;
[1(R)-cis]-3-chloro-N-[2-(2,5-difluorophenoxy)-1-methylethyl]-1,3-dimethylcyclobutanecarboxamide;
[1(R)-cis]-3-chloro-N-[2-(5-chloro-2-cyanophenoxy)-1-methylethyl]-1,3-dimethylcyclobutanecarboxamide; and
[1(R)-cis]-3-chloro-N-[2-(2-cyano-5-fluorophenoxy)-1-methylethyl]-1,3-dimethylcyclobutanecarboxamide.
Preferred 5. Compounds of Formula I above wherein
R1 is halogen or C1-C2 alkyl;
R2 is halogen or C1-C2 alkyl; and
R3 is Cl1-C2 alkyl optionally substituted with halogen;
R4 is CH3;
R5 is R6; and
R6 is naphthalenyl optionally substituted with one to three substituents selected from the group halogen, C1-C4 alkyl, C1-C4 haloalkoxy and cyano.
Preferred 6. Most preferred compounds of Preferred 5 include [1(R)-cis]-3-chloro-1,3-dimethyl-N-[1-(2-naphthalenyl)ethyl]cyclobutanecarboxamide.
Preferred mixtures include mixtures (e.g., a 1:1 molar mixture) of [1(R)-cis]-N-[1-(4-bromophenyl)ethyl]-3-chloro-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide with [1(R)trans]-N-[1-(4-bromophenyl)ethyl]-3-chloro-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide. Preferred mixtures also include mixtures (e.g., a 1:1 molar mixture) of [1(R)-cis]-3-chloro-N-[2-(2-fluorophenoxy)-1-methylethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide with [1(R)-trans]-3-chloro-N-[2-(2-fluorophenoxy)-1-methylethyl]-3-methyl-1-(trifluoromethyl)cyclobutanecarboxamide.
Of note are compounds of Formula I where R1 is halogen or C1-C2 alkyl. Also of note are compounds of Formula I were R2 is halogen or C1-C2 alkyl. Further of note are compounds of Formula I were R6 is phenyl optionally substituted with one to two substituents selected from the group halogen, C1-C4 alkyl, CF3, C1-C4 haloalkoxy and cyano.
This invention also relates to fungicidal compositions comprising fungicidally effective amounts of the compounds of the invention and at least one of a surfactant, a solid diluent or a liquid diluent. The preferred compositions of the present invention are those which comprise the above preferred compounds.
This invention also relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, to a flooded rice paddy, or to the plant seed or seedling, a fungicidally effective amount of the compounds of the invention (e.g., as a composition described herein). The preferred methods of use are those involving the above preferred compounds.
The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-12. The definitions of X, X1 and R1-R14 in the compounds of Formulae 1-20 below are as defined above in the Summary of the Invention or in the schemes below. 
Cyclobutane carboxylic acids of Formula 1 are converted to the corresponding acid chlorides of Formula 2. This reaction can be carried out by using 1-10 equivalents of any of a variety of chlorinating reagents, such as thionyl chloride or oxalyl chloride, either neat or in inert solvent, over a wide temperature range. Examples of suitable solvents include dichloromethane, toluene and dichloroethane. Generally, the reaction is carried out at a temperature between 0xc2x0 C. and the boiling point of the reaction mixture for 0.1 to 72 h. Optionally, promoters, such as N,N-dimethylformamide (DMF), can be used in conjunction with the chlorinating reagent. The acid chlorides are in turn reacted with an amine of Formula 3 to give the amide I. The process can be carried out over a wide temperature range in a wide variety of solvents. Generally, the reaction is carried out at a temperature between xe2x88x9230xc2x0 C. and 60xc2x0 C. for 0.1 to 72 h. Optionally, 1-10 equivalents of an acid acceptor, such as sodium carbonate or triethylamine, can be added to neutralize acid that is formed. The reaction can be done in an inert solvent, such as dichloromethane, toluene, tetrahydrofuran (THF), dioxane, or DMF, in water, or in a two component solvent mixture, such as 1:1 dioxane-water. 
Cyclobutane carboxylic acids of Formula 1 are also converted to the corresponding mixed anhydrides of Formula 4. This reaction can be carried out by using 1-10 equivalents of a variety of carbonic acid derivatives, such as ethyl chloroformate or isobutyl chloroformate, in an inert solvent. Generally, the reaction is carried out at a temperature between xe2x88x9230xc2x0 C. and 20xc2x0 C. for 0.1 to 72 h. Often, the reaction is performed along with 1-10 equivalents of an acid acceptor, such as triethylamine or N-methyl morpholine, to neutralize acid that is formed. Examples of suitable solvents include dichloromethane, toluene, tetrahydrofuran (THF), dioxane, or DMF. The mixed anhydrides are in turn reacted with an amine of Formula 3 to give the amide I. The process can be carried out over a wide temperature range in a wide variety of solvents. Generally, the reaction is carried out at a temperature between xe2x88x9230xc2x0 C. and 60xc2x0 C. for 0.1 to 72 h. 1-10 Equivalents of an acid acceptor, such as triethylamine or N-methyl morpholine, are also often added to neutralize acid that is formed. The reaction can be done in any inert solvent such as dichloromethane, toluene, or dioxane. 
Cyclobutane carboxylic acids of Formula 1 can also be directly coupled with amines of Formula 3 in the presence of 1-10 equivalents of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI), 1,1xe2x80x2-carbonylbis[3-methyl-1H-imidazolium] (1:2) salt with trifluoromethanesulfonic acid (CBMIT) or, Nxe2x80x2-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine monohydrochloride (EDCI). The process can be carried out over a wide temperature range in a wide variety of solvents. Generally, the reaction is carried out at a temperature between xe2x88x9230xc2x0 C. and 20xc2x0 C. for 0.1 to 72 h. The reaction can be done in any inert solvent such as dichloromethane, toluene, acetonitrile, or dioxane.
One skilled in the art will recognize that there are many other methods for the preparation of amides from carboxylic acids and amines which are not specified here. The intent of this part of the description of the invention is only to identify some potentially useful methods for the preparation of compounds of Formula I and is not intended to identify every possible method.
Cyclobutne carboxylic acids of Formula 1 are known or can be prepared by a variety of methods. The preparation of cyclobutane carboxylic acid of Formula 1 where R1=Cl, R2=R3=H is disclosed in the literature (Hall, H. K.; Blanchard, E. P.; Cherkofsky, S. C.; Sieja, J. B.; and Sheppard, W. A. J. Amer. Chem. Soc. 1971, 93, 110-20). The preparation of cyclobutane carboxylic acid of Formula 1 where R1=Cl, R2=CH3, and R3=H is disclosed in the literature (Hall, H. K., Jr.; Smith, C. D.; Blanchard, E. P.; Cherkofsky,S. C.; and Sieja, J. B. J. Amer. Chem. Soc. 1971, 93, 121-9). The preparation of cyclobutane carboxylic acids of Formula 1 where R1=Cl, R2=CH3 or H and R3=CH3 or CF3 is disclosed in the literature (Hall, H. K., Jr.; Blanchard, E. P.; and Martin, E. L. Macromolecules 1971, 4, 142-6). 
Additional cyclobutane carboxylic acids of Formula 1a can be prepared by the addition of hydrohalogen acids to 3-methylene-1-cyclobutane carboxylic acids of Formula 5 (Scheme 4). This reaction can be carried out using any strong acid, such as hydrogen chloride or hydrogen bromide, over a wide temperature range. The strong acid used can be either as an aqueous solution or as a gas, either with or without solvent. The reaction can be done at atmospheric pressure or under pressure in a sealed reaction vessel. Generally, the reaction is carried out at a temperature between 20xc2x0 C. and the reflux temperature of the mixture using a concentrated aqueous solution of the acid for 0.1 to 72 h. Any solvent that is not reactive to strong acid is suitable, examples being water, methanol, ethanol, or dioxane. 
Cyclobutane carboxylic esters of Formula 8 can be prepared by the addition of two molecules of fluorine to ketone intermediate of Formula 7. This transformation can be done with a number of different fluorinating reagents, such as (diethylamino)sulfur trifluoride (DAST), over a wide temperature range. Generally, the reaction is carried out at a temperature between xe2x88x9240xc2x0 C. and ambient temperature, in an inert solvent, such as dichloromethane, 1,2-dichloroethane, or toluene. Intermediate of Formula 7 can be formed by the treatment of intermediate of Formula 6 with ozone, followed by treatment with of the solution with a reducing reagent, such as dimethylsulfide. This reaction can be carried out in any convenient solvent that is not subject to ozone oxidation, such as dichloromethane, 1,2-dichloroethane, or toluene, at a temperature between xe2x88x9290 to xe2x88x9260xc2x0 C. 
3-Methylene-1-cyclobutane carboxylic acids of Formula 5 can be prepared by the hydrolysis of the corresponding cyclobutane carbonitrile of Formula 9 (Scheme 6). This reaction can be carried out by using aqueous hydroxide solution or by any strong aqueous acid, such as hydrogen chloride or hydrogen bromide, over a wide temperature range. Generally, the reaction is carried out at a temperature between 20xc2x0 C. and the reflux temperature of the mixture for 0.1 to 72 h. The reaction can be done at atmospheric pressure or under high pressure in a sealed reaction vessel. Generally, hydrolysis using base is done at atmospheric pressure at the boiling point of the mixture and hydrolysis with acid is done at 100xc2x0 C. in a sealed reaction vessel. Hydrolysis using aqueous hydrohalogenic acid will give the cyclobutane carboxylic acid of Formula 1a directly. 
3-Methylene-1-cyclobutane carbonitriles and esters of Formula 11 can be prepared by the thermal cycloaddition of allene to the appropriately substituted acrylonitrile or acrylate ester of Formula 10 (Scheme 7). This reaction can be carried out under pressure in a sealed reaction vessel over a wide temperature range. Generally, the reaction is carried out at a temperature above 100xc2x0 C. in a pressurized reaction vessel for 0.5 to 72 h with 1-100 equivalents of allene. Optionally, an inert solvent, such as benzene, can be used. Optionally, 0.01-1 equivalent of some polymerization inhibitor, such a hydroquinone or 4-methoxyphenol, can be used. Appropriately substituted acrylonitriles or acrylate esters of Formula 10 are commercially available or known in the literature. For example, the preparation of ethyl xcex1-fluoromethyl-acrylate is reported by Powell and Graham (J. Polymer Sci. Part A, 1965, 3, 3451-8).
Amines of Formula 3 are known or can be prepared by a variety of methods. Amines of Formula 3 where R4=CH3, R5=R6 and R6=phenyl, 4-chlorophenyl, 4-bromophenyl, 1-naphthyl, or 2-naphthyl are commercially available. Additional amines of Formula 3 can be prepared from the corresponding ketones or aldehydes by reductive amination (Borch reduction) as shown in Scheme 8. 
R5 is R6 wherein R6 is other than substituted pyrrole, CH(R8)OR6, CH(R8)CH(R7)R6 or C(R8)xe2x95x90C(R7 )R6 wherein R6 is other than substituted pyrrole 
R12 and R13 are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, Si(CH3)3, cyano, NHC(xe2x95x90O)R9 or NHC(xe2x95x90S)R9 
The reductive amination can be carried out using 1-10 equivalents of an ammonium halide or acetate salt, such as ammonium acetate, and 1-10 equivalents of a hydride reducing agent, such as sodium cyanoborohydride. The reaction can be run in any suitable solvent, such as methanol, ethanol, THF or dichloromethane. Optionally, an acid, such as HCl or p-toluenesulfonic acid, can be added portionwise during the course of the reaction so as to maintain a pH of 3-5. Typical temperatures for the reductive amination range from xe2x88x925xc2x0 C. to 60xc2x0 C. Acetyl substituted benzenes (acetophenones) and acetyl substituted heterocycles are known and many are commercially available. 
Compounds of Formula 12a can be prepared by the alkylation of variously substituted compounds of Formula 14 with xcex1-chloro ketones of Formula 13 (Scheme 9). This reaction may be done over a wide variety of temperatures in a range of solvents. Generally, the reaction is performed at temperatures ranging from 20xc2x0 C. to the boiling point of the mixture. Optionally, 1-10 equivalents of an acid acceptor, such as potassium carbonate or triethylamine, is added to neutralize acid that is formed. Suitable solvents include acetone, methyl ethyl ketone, THF, DMF, or water. 
A method of synthesis of amines of Formula 3a is reaction of the corresponding phthalimides of Formula 16 with hydrazine (Scheme 10). The phthalimides of Formula 16 are prepared in turn from hydroxy phthalimides of Formula 15 and the appropriately substituted compound of Formula 14 in the presence of 1-2 equivalents of triphenylphosphine and 1-2 equivalents of a dialkyl azodicarboxylate, such as diethyl azodicarboxylate (DEAD). The reaction is generally run in an inert solvent such as dichloromethane or THF at a temperature range between xe2x88x9230xc2x0 C. and the boiling point of the mixture. The resulting phthalimides of Formula 16 are converted to the amines of Formula 3a by the reaction of 1-10 equivalents hydrazine or some other primary amine. This reaction is generally run in a polar solvent, such as ethanol or THF, at a temperature range of between 20xc2x0 C. and the boiling point of the mixture. 
The amines of Formula 3b can be prepared by hydrolysis of the corresponding carbamates of Formula 19 (Scheme 11). These carbamates can in turn be made by coupling a suitably protected allylic amines of Formula 17 with aromatic bromides of iodides of Formula 18. Appropriate catalysts for the coupling reaction (Heck reaction) include PdCl2 and Pd(OAc)2 complexed with 2-4 fold excess phosphine ligand such as triphenylphosphine. Typically 1-10 mol % of the appropriate catalyst is used. The reactions are performed between 0xc2x0 C. and 100xc2x0 C. with 1-3 equivalents of base, such as potassium carbonate or triethylamine. Often 10-50 mol % of a phase transfer catalyst, such as tetrabutylammonium bromide, is used in the reaction mixture. Typical solvents include acetonitrile and DMF. Carbamates of Formula 19 wherein R14 is typically t-butyl or benzyl are removed by standard methods set out in the literature (see Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). 
Amines of Formula 3c are available from the corresponding carbamates of Formula 20 which are in turn accessible from the allylic carbamates of Formula 19 (Scheme 12). Reduction of the allylic carbamate is conveniently done by hydrogenation in the presence of a metal catalyst, such as 5% palladium impregnated on carbon. This reduction can be carried out over a wide temperature range in a variety of solvents under pressure of hydrogen gas. Generally hydrogenations are carried out at 20xc2x0 C. under 30 psi of hydrogen. Any solvent compatible with hydrogenation is suitable, for example THF, methanol, ethanol, or water. Carbamates of Formula 20 wherein R14 is typically t-butyl or benzyl are removed by standard methods set out in the literature (see Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley; New York, 1991). Hydrogenation of the carbamate of Formula 19 where R14 is benzyl will simultaneously reduce the double bond and remove the carbamate functional group to give the amine of Formula 3c directly.
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I.
One skilled in the art will also recognize that compounds of Formula I and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.